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Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy
Published on: November 30, 2018
Human Fibrinogen Inhibits Amyloid Assembly of Most Phenol-Soluble Modulins from Staphylococcus aureus
Zahra Najarzadeh1, Janni Nielsen1, Azad Farzadfard1
1Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Abstract:
Functional amyloids are highly organized protein/peptide structures that inter alia promote biofilm formation in different bacteria. One such example is provided by a family of 20-45 residue-long peptides called phenol-soluble modulins (PSMs) from Staphylococcus aureus. External components such as eukaryotic host proteins, which alter self-assembly of bacterial amyloids, can affect the biofilm matrix. Here, we studied the effect of the highly prevalent human plasma protein fibrinogen (Fg) on fibrillation of PSMs. Fg inhibits or suppresses fibrillation of most PSMs tested (PSMα1, PSMβ1, and PSMβ2) except for PSMα3, whose already rapid aggregation is accelerated even further by Fg but leads to amorphous β-rich aggregates rather than fibrils. Fg also induces PSMβ2 to form amorphous aggregates and diverts PSMα1 into off-pathway oligomers which consist of both Fg and PSMα1 and cannot seed fibrillation. Peptide arrays showed that Fg bound to the N-terminus of PSMα1, while it bound to the entire length of PSMα3 (except the C terminus) and to the C-termini of PSMβ1 and PSMβ2. The latter peptides are all positively charged, while Fg is negatively charged at physiological pH. The positive charges complement Fg's net negative charge of -7.6 at pH 7.4. Fg's ability to inhibit PSM fibrillation reveals a potential host-defense mechanism to prevent bacterial biofilm growth and infections in the human body.
Insights
Human fibrinogen (Fg) interferes with the self-assembly of phenol-soluble modulins (PSMs), bacterial amyloid peptides. This interaction may represent a host defense mechanism against Staphylococcus aureus biofilm formation.
Area of Science:
- Microbiology
- Biochemistry
- Structural Biology
Background:
- Functional amyloids, like phenol-soluble modulins (PSMs) from Staphylococcus aureus, are crucial for bacterial biofilm formation.
- Eukaryotic host proteins can modulate bacterial amyloid self-assembly and impact biofilm structure.
Purpose of the Study:
- To investigate the effect of human fibrinogen (Fg), a prevalent plasma protein, on the fibrillation of Staphylococcus aureus PSMs.
- To elucidate the molecular mechanisms underlying Fg-PSM interactions and their impact on amyloid formation.
Main Methods:
- In vitro fibrillation assays were used to study the self-assembly of various PSM peptides in the presence of Fg.
- Peptide arrays were employed to determine the binding sites of Fg on different PSMs.
- Analysis of aggregate morphology and composition was performed.
Main Results:
- Fg inhibited or suppressed the fibrillation of PSMα1, PSMβ1, and PSMβ2.
- Fg accelerated the aggregation of PSMα3, leading to amorphous aggregates instead of fibrils.
- Fg induced off-pathway oligomers with PSMα1 and caused PSMβ2 to form amorphous aggregates.
- Fg binding sites varied across different PSMs, correlating with charge complementarity at physiological pH.
Conclusions:
- Human fibrinogen significantly alters PSM fibrillation, inhibiting or modifying aggregate formation.
- Fg's interaction with PSMs, particularly its binding to charged regions, suggests a potential host-defense mechanism against bacterial biofilms.
- Understanding these interactions could lead to novel strategies for combating Staphylococcus aureus infections.
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